Does metformin decrease blood pressure in patients with Type 2 diabetes intensively treated with insulin?

AIMS: We investigated in a double-blind study whether metformin reduces blood pressure (BP) in patients with Type 2 diabetes intensively treated with insulin. METHODS: A total of 220 patients with Type 2 diabetes were asked to undergo 24-h ambulatory BP monitoring (24-h ABPM). One hundred and eighty-two gave informed consent. Eighty-nine were randomized to metformin and 93 to placebo. Thirty-five subjects dropped out (13 placebo, 22 metformin users); 147 patients underwent a second 24-h ABPM, 16 weeks after randomization. RESULTS: Systolic BP (SBP), diastolic BP (DBP), pulse BP (PP), mean BP (MP) and heart rate (HR) were measured as office BP measurements and as 24-h ABPM for 24-h, day and night. Office BP measurements did not differ significantly between the placebo- and metformin-treated groups for any BP measure, but showed a non-significant trend for SBP reduction with metformin use (mean baseline-adjusted difference, metformin minus placebo: -4.2 mmHg, 95% CI, -9.9 to +1.5; P = 0.15). The baseline-adjusted differences of the ambulatory measurements were -0.2 mmHg (95% CI, -2.9 to +2.6) for the 24-h SBP, and +1.1 mmHg (95% CI, -0.7 to +2.8) for the 24-h DBP. On the whole, BP differences between metformin- and placebo-treated groups were not statistically significant. The only significant difference was for night-time PP (baseline-adjusted difference: -2.2 mmHg; 95% CI, -4.2 to -0.2). These results were not different after adjustment for age and diabetes duration, or for (changes in) body mass index, glycated haemoglobin, insulin dose or plasma homocysteine. CONCLUSION: Metformin does not significantly affect BP in patients with Type 2 diabetes intensively treated with insulin.     

Comparison of vildagliptin and metformin monotherapy in elderly patients with type 2 diabetes: a 24-week, double-blind, randomized trial

Aims: The study evaluated the efficacy and tolerability of the dipeptidyl peptidase‐4 inhibitor, vildagliptin, and metformin in drug‐naïve elderly patients with type 2 diabetes. The primary objective was to demonstrate non‐inferiority of vildagliptin vs. metformin in glycated haemoglobin (HbA_1c) reduction. Methods: This was a double‐blind, randomized, multicentre, active‐controlled, parallel‐group study of 24‐week treatment with vildagliptin (100 mg daily, n = 169) or metformin (titrated to 1500 mg daily, n = 166) in drug‐naïve patients with type 2 diabetes aged ≥65 years (baseline HbA_1c 7–9%). Results: Participants had a mean age of 71 years, known duration of diabetes of 3 years and mean baseline HbA_1c of 7.7%. At end‐point, vildagliptin was as effective as metformin, improving HbA_1c by ?0.64 ± 0.07% and ?0.75 ± 0.07%, respectively, meeting the predefined statistical criterion for non‐inferiority (upper limit of 95% confidence interval for between‐treatment difference ≤0.3%). Body weight changes were ?0.45 ± 0.20 kg in vildagliptin‐treated patients (p = 0.02) and ?1.25 ± 0.19 kg in metformin‐treated patients (p < 0.001; p = 0.004 vs. vildagliptin). The proportion of patients experiencing an adverse event (AE) was 44.3 vs. 50.3% in patients receiving vildagliptin and metformin respectively. Gastrointestinal (GI) AEs were significantly more frequent with metformin (24.8%) than with vildagliptin (15.0%, p = 0.028), mainly driven by a 4.4‐fold higher incidence of diarrhoea. A low incidence of hypoglycaemia was observed in both treatment groups (0% with vildagliptin and 1.2% with metformin). Conclusions: Vildagliptin is an effective and well‐tolerated treatment option in elderly patients with type 2 diabetes, demonstrating similar improvement in glycaemic control as metformin, with superior GI tolerability.     

Fasting plasma glucose and HbA1c as risk factors for Type 2 diabetes

Aims We examined the value of combining fasting plasma glucose (FPG) and glycated haemoglobin (HbA_1c) as a predictor of diabetes, using the new American Diabetes Association (ADA) criteria of FPG and lower cut‐off point of HbA_1c. Methods A retrospective cohort study was conducted from 1998 to 2006, inclusive, in 10 042 persons (55 884 person‐years), with a mean age of 53.0 years at baseline. The cumulative incidence of diabetes (defined either as an FPG ≥ 7.0 mmol/l or as clinically diagnosed diabetes) was measured. Results The cumulative incidence and incidence density of diabetes were 3.7% (368 cases) and 6.6/1000 person‐years over a mean follow‐up period of 5.5 years. The cumulative incidence of diabetes in subjects with impaired fasting glucose (IFG) and HbA_1c 5.5–6.4% was 24.8% (172/694 persons) compared with 0.4% (25/6698 persons), 2.5% (15/605 persons), 7.6% (156/2045 persons) in those with normal fasting glucose (NFG) and HbA_1c < 5.5%, NFG and HbA_1c 5.5–6.4% and IFG and HbA_1c < 5.5%, respectively. The hazard ratio for diabetes, adjusted for possible confounders, was 7.4 (95% confidence interval, 4.70 to 11.74) for those with NFG and HbA_1c 5.5–6.4%, 14.4 (11.93 to 27.79) for those with IFG and HbA_1c < 5.5% and 38.4 (24.63 to 59.88) for those with IFG and HbA_1c 5.5–6.4%. Conclusions The combination of FPG and HbA_1c identifies individuals who are at risk of progression to Type 2 diabetes at the new ADA criteria of FPG and a lower cut‐off point of HbA_1c than previous studies.     

Health status and hypoglycaemia with insulin degludec versus insulin glargine: a 2‐year trial in insulin‐naïve patients with type 2 diabetes

Insulin degludec (IDeg) is a new basal insulin with an ultra‐long and stable glucose‐lowering effect. We compared once‐daily IDeg and insulin glargine (IGlar), both in combination with metformin ± dipeptidyl peptidase‐4 inhibitors, in a 52‐week, open‐label, treat‐to‐target trial in patients with type 2 diabetes followed by a 52‐week extension trial in which subjects [n = 725/1030 (70.4%)] maintained their initial randomised treatment. Health status was assessed at baseline and 105 weeks using the Short Form‐36 (SF‐36 v2) questionnaire. SF‐36 scores were analysed (ITT population) using anova , with adjustments for covariates. At 105 weeks, the overall physical component score was significantly better with IDeg versus IGlar [treatment contrast (TC): 1.1 (0.1; 2.1)_95%CI, p < 0.05]. This was largely because of significantly better physical functioning [TC: 1.1 (0.0; 2.3)_95%CI, p < 0.05] and bodily pain sub‐domain scores [TC: 1.5 (0.2; 2.9)_95%CI, p < 0.05]. Improvements in health status with IDeg compared to IGlar were maintained after 2 years.     

Comparison of vildagliptin and pioglitazone in patients with type 2 diabetes inadequately controlled with metformin

Aim: To compare the tolerability and efficacy of vildagliptin to pioglitazone as add‐on therapy in patients with type 2 diabetes inadequately controlled with metformin monotherapy over 1‐year duration. Methods: This 52‐week, multicentre, randomized, active‐controlled study compared vildagliptin (50 mg b.i.d., n = 295) and pioglitazone (30 mg daily, n = 281) in patients with inadequate glycaemic control [haemoglobin A1c (HbA_1c) 7.5–11%] receiving a stable dose of metformin (≥1500 mg). The primary objective was to demonstrate non‐inferiority of vildagliptin at 24 weeks in the change in HbA_1c from baseline. The objective of the additional 28 weeks of the study was to assess long‐term safety, while also assessing mean change from baseline to study end in HbA_1c, fasting plasma glucose and body weight. Results: When added to a stable dose of metformin (mean baseline dose approximately 2 g/day), the non‐inferiority of HbA_1c lowering of vildagliptin to pioglitazone over 24 weeks was established at the non‐inferiority margin of 0.3% (between‐group difference = 0.1%). During the remaining 28 weeks, comparable HbA_1c decreases were recorded in both groups. Overall adverse event (AE) rates were similar in both groups, as was the occurrence of peripheral oedema. Hypoglycaemia occurred rarely in both groups. Serious AEs occurred more frequently with pioglitazone group. While mean body weight increased significantly in the pioglitazone group (+2.6 kg) from baseline, there was no significant weight gain with vildagliptin (+0.2 kg). Conclusions: When added to metformin, vildagliptin demonstrates favourable safety and tolerability over 1 year. Vildagliptin provided additional HbA_1c lowering to that achieved with metformin alone and comparable to that achieved with pioglitazone, with only pioglitazone causing weight gain.     

Associations of HbA1c and educational level with risk of cardiovascular events in 32 871 drug‐treated patients with Type 2 diabetes: a cohort study in primary care

Aims

To explore the association of HbA_1c and educational level with risk of cardiovascular events and mortality in patients with Type 2 diabetes.

Methods

A cohort of 32 871 patients with Type 2 diabetes aged 35 years and older identified by extracting data from electronic patient records for all patients who had a diagnosis of Type 2 diabetes and had glucose‐lowering agents prescribed between 1999 and 2009 at 84 primary care centres in Sweden. Associations of mean HbA_1c levels and educational level with risks of cardiovascular events and all‐cause mortality were analysed.

Results

The associations of HbA_1c with risk of all‐cause and cardiovascular mortality were J‐shaped, with the lowest risk observed for cardiovascular mortality at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. The lowest risk observed for all‐cause mortality was at an HbA_1c level of 51 mmol/mol (6.8%) for subjects on oral agents and 56 mmol/mol (7.3%) in insulin‐treated patients. There was an increased risk for cardiovascular death [hazard ratio 1.6 (1.2–2.1), P = 0.0008] at the lowest HbA_1c decile for subjects in the low education category. For subjects with higher education there was no evident J curve for cardiovascular death [hazard ratio 1.2 (0.8–1.6), P = 0.3873].

Conclusions

Our results lend support to the recent American Diabetes Association/ European Association for the Study of Diabetes position statement that emphasizes the importance of additional factors, including the propensity for hypoglycaemia, which should influence HbA_1c targets and treatment choices for individual patients. (Clinical Trials Registry No; NCT 01121315)     

Addition of sitagliptin to ongoing metformin monotherapy improves glycemic control in Japanese patients with type 2 diabetes over 52 weeks

Aims/Introduction

The efficacy and safety of sitagliptin, a highly selective dipeptidyl peptidase‐4 inhibitor, when added to metformin monotherapy was examined in Japanese patients with type 2 diabetes.

Materials and Methods

In this 52‐week, add‐on to metformin study, 149 patients were randomly assigned to receive sitagliptin 50 mg or placebo once daily in a double‐blind fashion for 12 weeks. Thereafter, all patients who completed the double‐blind period of the study received open‐label sitagliptin 50 mg once daily for 40 weeks, with the investigator option of increasing sitagliptin to 100 mg once daily for patients who met predefined glycemic thresholds.

Results

After 12 weeks of treatment, the mean change from baseline in glycated hemoglobin (HbA1c) significantly decreased with sitagliptin relative to placebo (between‐group difference [95% confidence interval] = −0.7% [−0.9 to −0.5] P < 0.001). At week 12, the mean changes in 2‐h post‐meal glucose (−2.6 mmol/L [−3.5 to −1.7]) and fasting plasma glucose (−1.0 mmol/L [−1.3 to −0.6]) also decreased significantly with sitagliptin relative to placebo (P < 0.001 for both). Significant improvements from baseline in glycemic control were also observed in the open‐label period through to week 52. There were no differences between treatment groups in the incidence of adverse events (AEs), including hypoglycemia and predefined gastrointestinal AEs (nausea, vomiting and diarrhea) during the double‐blind period, with similar findings in the open‐label period.

Conclusions

Over a period of 52 weeks, the addition of sitagliptin once‐daily to ongoing metformin therapy was efficacious and generally well tolerated in Japanese patients with type 2 diabetes. This trial was registered with ClinicalTrials.gov (no. NCT00363948).     

The locus of control in patients with Type 1 and Type 2 diabetes managed by individual and group care

Aims The locus of control theory distinguishes people (internals) who attribute events in life to their own control, and those (externals) who attribute events to external circumstances. It is used to assess self‐management behaviour in chronic illnesses. Group care is a model of systemic group education that improves lifestyle behaviour and quality of life in patients with Type 1 and Type 2 diabetes. This study investigated the locus of control in Type 1 and Type 2 diabetes and the possible differences between patients managed by group care and control subjects followed by traditional one‐to‐one care. Methods Cross‐sectional administration of two questionnaires (one specific for diabetes and one generic for chronic diseases) to 83 patients followed for at least 5 years by group care (27 Type 1 and 56 Type 2) and 79 control subjects (28 Type 1 and 51 Type 2) of similar sex, age and diabetes duration. Both tools explore internal control of disease, the role of chance in changing it and reliance upon others (family, friends and health professionals). Results Patients with Type 1 diabetes had lower internal control, greater fatalistic attitudes and less trust in others. Patients with either type of diabetes receiving group care had higher internal control and lower fatalism; the higher trust in others in those with Type 1 diabetes was not statistically significant. The differences associated with group care were independent of sex, age and diabetes duration. Conclusions Patients with Type 1 diabetes may have lower internal control, fatalism and reliance upon others than those with Type 2 diabetes. Receiving group care is associated with higher internal control, reduced fatalism and, in Type 1 diabetes, increased trust in others.     

Effects of improved glycaemic control maintained for 3 months on cognitive function in patients with Type 2 diabetes

Background and aim In a previous study we failed to find beneficial short‐term effects of improved glycaemic control on cognitive functioning in patients with Type 2 diabetes mellitus. A subgroup of the entire sample was tested again to examine the effect of longer‐lasting improvement of metabolic control on cognitive functioning. Methods The cognitive performance of 26 patients with Type 2 diabetes was assessed at baseline and 3 months after discharge. Thirteen controls were tested at the similar time‐points. Attention/concentration, psychomotor speed, verbal fluency, verbal memory and depressive symptoms were assessed. Improved glycaemic control was generally achieved with insulin therapy (20/26). Results At baseline, there was a trend for diabetic patients to perform worse than controls. Both groups improved significantly over 3 months in several measures. However, diabetic patients did not improve more than controls. Conclusions In individuals with long‐standing Type 2 diabetes, previous reports of improved cognitive capacity following restoration and maintenance of near‐normoglycaemia were not confirmed. This might relate to the type of anti‐diabetic therapy.     

Serum angiotensin‐converting enzyme and frequency of severe hypoglycaemia in Type 1 diabetes: does a relationship exist?

AIMS: An association has been described between elevated serum angiotensin-converting enzyme (ACE) and an increased risk of severe hypoglycaemia (SH). To ascertain whether this reported association could be replicated in a different country, it was re-examined in 300 individuals with Type 1 diabetes. METHODS: People with Type 1 diabetes, none of whom was taking renin-angiotensin system blocking drugs, were recruited. Participants recorded the frequency with which they had experienced SH. Glycated haemoglobin (HbA(1c)) and serum ACE were measured. The difference in the incidence of SH between different quartiles of ACE activity and the relationship between serum ACE and SH were examined using non-parametric statistical tests and a negative binomial model. RESULTS: Data were obtained from 300 patients [158 male; HbA(1c) median (range) 8.2% (5.2-12.8%), median age 36 years (16-88); duration of diabetes 14.5 years (2-49)]. The incidence of SH was 0.93 episodes per patient year. The mean incidence of SH in the top and bottom quartiles of ACE activity was 0.5 and 1.7 episodes per patient year, respectively, but this difference was not statistically significant (P = 0.075). Spearman's test showed a very weak, although statistically significant, association between serum ACE level and SH incidence (r = 0.115, P = 0.047). The binomial model also showed a statistically significant (P = 0.002), but clinically weak, relationship between serum ACE and SH. CONCLUSIONS: The present survey showed a weak relationship between serum ACE and the frequency of SH, the clinical relevance of which is unclear. This limits the proposed role for serum ACE as an index of risk for SH.